alpha, alpha-disubstituted-beta-amino propionic acids



United States Patent 3,328,436 u,a-DlSUBSTlTUTED-B- MlNO PRGPIONIC ACIDS Gustav Erlemann, Riehen, Peter Fahrni, Binningen, and

Otto Schnider, Basel, Switzerland, assignors to Hottmann-La Roche Inc, Nutley, N.J., a corporation of New Jersey No Drawing. Filed Dec. 6, 1963, Ser. No. 328,483 Claims priority, application Switzerland, Dec. 21, 1962, 15,071/62 7 Claims. (Cl. 260-404) This invention relates in general to a novel class of compounds and to a process for the production thereof. More particularly, the invention relates to a class of novel amino carboxylic acids, to a process for the production thereof and to the use of such compounds.

The novel amino carboxylic acid compounds of this invention have the general formula RH COOH I in which the symbol R represents a saturated hydrocarbon residue having a carbon chain length of at least 7 carbon atoms; and in which the symbol R represents a saturated hydrocarbon residue having a chain length of from 1 to carbon atoms. Additionally, this invention includes salts of amino carboxylic acids of Formula I.

The saturated hydrocarbon residues which, in Formula I are represented by the symbol R are straight chain, as well as branched chain, saturated hydrocarbon residues having a chain length of at least about 7 carbon atoms. The compounds of the preferred embodiment of the invention contain, as the R substituent, an alkyl group having a carbon chain length of from about 8 to 22 carbon atoms. Representative of such alkyl groups are the octyl, nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl, eicosyl and docosyl radicals.

The saturated hydrocarbon residues which, in Formula I are represented by the symbol R include straight chain, as well as branched chain, saturated hydrocarbon residues having a carbon chain length of from 1 to 10 carbon atoms. The preferred compounds of the invention, however, contain, as the R substituent, a lower alkyl group, either straight chain or branched chain, having a carbon chain length of from 1 to 8 carbon atoms. Among the saturated hydrocarbon residues which are represented in Formula I by the symbol R are, for example, methyl, ethyl, propyl, n-butyl, isobutyl, n'pentyl, isoamyl, hexyl, heptyl and octyl radicals.

As indicated heretofore, the present invention embraces also salts of the amino carboxylic acids of Formula 1. Such salts include internal salts which are obtainable as a result of the amphoteric character of the amino carboxylic acids, as well as salts of the Formula I compounds with mineral acids, such as, hydrochloric acid, sulfuric acid, phosphoric acid; organic acids, such as, citric acid, acetic acid, benzoic acid; and with strong alkalis, such as ammonia, monoethanol amine, triethanol amine, 2-amino-2-methyl-1,3-propanediol.

The compounds of Formula I are readily obtained. In general, the process for their production comprises reacting a compound having the formula in which the symbol R represents an esterified carboxyl group; in which the symbol R represents a saturated ice or unsaturated hydrocarbon residue having a carbon chain length of at least 7 carbon atoms; and in which R represents a saturated or unsaturated hydrocarbon residue containing from 1 to 10 carbon atoms, with a reducing agent, following which the reduction product is treated with a hydrolyzing agent. If desired, the amino carboxylic acid which is thus obtained can be converted into a salt.

In the reduction step of the process described in the preceding paragraph, the cyano group of the starting Formula II compound is converted into an aminomethyl group. In the hydrolysis step, the esterified carboxyl group 15 split to yield the desired amino carboxylic acid of Formula I. The amino carboxylic acid which is obtained by the sequential reduction and hydrolysis step can be converted into a salt, if desired.

It should be understood that while the reduction step and the hydrolysis step described in the preceding paragraph are each essential to the present process, the sequence in which they are carried out, is not critical to the operability of the invention. Thus, for example, in the preceding paragraph, it is disclosed that the compound of Formula II is first reduced and that the reduction product is, subsequently, hydrolyzed. As an alternate means of carrying out the present invention, the compound of Formula II can be reacted first, if desired, with the hydrolyzing agent and the hydrolysis product, thus obtained, subsequently reacted with the reducing agent. In the preferred embodiment of the invention, however, the cyano group of the Formula II compound is first reduced to the aminomethyl group, following which the reduction product is hydrolyzed.

The reduction step of the present process can be carried out using methods known, per se. In general, one can employ any reduction procedure which is applicable to the reduction of cyano carboxylic acids or carboxylic acid esters to the corresponding amino carboxylic acids or carboxylic acid esters. Preferably, however, the reduction is effected with hydrogen in the presence of a suitable hydrogenation catalyst. In such a reduction procedure, there can be used as the catalyst platinum, palladium or nickel catalysts. Raney-nickel catalyst is preferably employed in this step. In the alternative, Raney-cobalt can be used as the catalyst in the reduction step.

The catalytic reduction described in the preceding paragraph can be carried out, if desired, under pressure. The use of pressure is not, however, necessary. Moreover, in the reduction step, it is convenient to employ a solvent such as an alcohol, for example ethyl alcohol or methyl alcohol, in the reaction system. The alcohol which corresponds to the ester group of the Formula II compound is preferably used as the solvent.

It has been observed that the reduction reaction proceeds in a very uniform fashion, with the result thgt the cyano group is reduced, almost exclusively, to the primary amino group. The formation of undesired hydrogenation products, that is, compounds having secondary or tertiary amino groups can, if necessary, be obviated, or at least minimized, by methods known, per se, for example, by carrying out the hydrogenation process in the presence of ammonia. During the course of the reduction reaction any unsaturated R and R substituents which are present in the Formula II starting material are themselves reduced to the corresponding saturated substituents, that is, to the saturated substituents represented by the symbols R and R in Formula I. As examples of this, the conversion of an allyl to an n-propyl group; the conversion of a methylallyl group to an isobutyl group; and the conversion of a 'y,'y-dimethallyl to an isoamyl group, can be mentioned.

The hydrolysis step of the present process, whereby the esterified carboxyl group of the Formula II starting material is converted to a free carboxyl group, can be carried out by methods known, per se. As the hydrolysis agent, there can be used either an acid or an alkali. It is most convenient, however, to carry out the hydrolysis reaction by adding an alcohol solution, for example, an ethyl alcohol solution, of the ester to be hydrolyzed to a solution of an alkali hydroxide and heating the mixture at reflux temperature. As the alkali, there can be used, for example, a solution of sodium hydroxide, potassium hydroxide, etc. in water.

The starting materials of Formula II can be readily obtained from the cyanoacetic ester. In producing these starting materials, the sodium salt of the cyanoacetic ester is reacted, in the presence of excess cyanoacetic ester, in alcohol with a R halogenide in which the symbol R, has the same meaning as in Formula II. Dodecyl bromide is illustrative of the R halogenides which are employed. Thereafter, a second substituent can be introduced into the monosubstituted cyanoacetic ester thus obtained, in a similar fashion. For example, an allyl group can be added thereto by reacting the monosubstituted cyanoacetic ester with allyl bromide.

In general, the amino carboxylic acids of Formula I are crystalline compounds which are very slightly soluble in water, cold ethanol, methanol or isopropanol. The melting points of these compounds are not very characteristic, since these have been observed to vary depending upon the rate at which the compound is heated. A majority of the compounds of this invention have been found to sinter at about from their true melting points. Fur= thermore, the present compounds have been observed to tolerate, in substance, temperatures of greater than 50 C. for a short period of time only. Upon heating to a temperature of about 100 C., the compounds of this invention form viscid polymerisates. The amino carboxylic acids of this invention possess unique and unusual properties which render them well suited for use for many and diverse purposes. It has been noted that these compounds are capable of thickening to gels non-polar organic solvents, such as, aliphatic hydrocarbons, for example, petrol, petroleum ether of various boiling ranges; halogenated aliphatic and aromatic hydrocarbons, such as, methylene chloride, chloroform, carbon tetrachloride; aromatic hydrocarbons, such as, benzene, toluene, xylene; nitrated hydrocarbons, for example, nitrobenzene; ethers, such as diethyl ether, dioxane, etc. A distinct and readily discernible viscosity-increasing effect is observed when one part by weight of the present compounds is added to 1,000 parts by volume of solvent. Moreover, for all practical purposes, a concentration of 0.5% or less of the present products in the solvent usually suffices to effect the desired thickening effect. Furthermore, mineral acid salts of the compounds of Formula I, such as the hydrochloride salt, produce a gelling effect in water. A further significant factor of the present invention is that the viscosity of the solutions or gels which are obtained using the present compounds is, under ordinary circumstances, not greatly affected by temperature changes. The thickening effect of the amino carboxylic acids, produced as described herein, can be counteracted by the addition of acids and bases, such as those mentioned above for salt formation. Counteraction becomes effective when more than the equivalent amounts of the acids and bases are added.

In slightly polar or non-polar low-boiling organic solvents, the products of this invention exert their gelling effect, to some extent, only after lengthy heating. In order to expedite the production of a gel in such instances, it is recommended that the crystalline compound of Formula I be heated in benzene to boiling to produce therein a clear gel. When this gel is evaporated subsequently under reduced pressure at a temperature of from about 40 C. to 60 C., there is obtained an amorphous product with enhanced gelation properties. Such amorphous compound, when heated in a slightly polar or non-polar low-boiling organic solvent, forms a gel very rapidly.

As a result of their properties, the present compounds are extremely useful as thickening or gelation agents in various fields. For example, the compounds of Formula I can be used in the pharmaceutical and cosmetic industries as thickeners and gelation agents for non-polar or slightly polar organic solvents. Furthermore, the present products, due to their thickening and gelation properties, are extremely well suited for use in connection with print colors, lacquers, paint colors, lubricating oils, stain-cleansing agents, etc. Specific examples showing the manner in which the present compounds are used will be found in the examples which follow hereinafter. However, the precise manner in which the present compounds are to be used will be immediately apparent to persons skilled in the art.

For a fuller understanding of the nature and objects of this invention, reference may be had to the following examples which are given merely as a further illustration of the invention and are not to be construed in a limiting sense.

Example 1 (a) 1090 grams of n-dodecyl-allyl-cyanoacetic acid ethyl ester, dissolved in 500 ml. of absolute alcohol, were hydrogenated in the presence of 200 grams of Raneynickel in a stirring autoclave at a temperature of C. and under 70 atmospheres of hydrogen. After the hydrogen uptake was completed, the reaction product was filtered, the solution which results after the filtration was evaporated under diminished pressure and the evaporation residue was subsequently distilled in a high vacuum. The a-n-dodecyl-ot-propyl-fi-amino-propionic acid ethyl ester, which was thus obtained, distilled as a colorless liquid at 150 C./0.15 mm. in a yield of 78% of theory.

(b) 687 grams of the oa-n-dodecyl-a-propyLfi-aminoprcpionic acid ethyl ester obtained, as described in the preceding paragraph, were dissolved in 3800 ml. of ethyl alcohol. Thereafter, a solution of 235 grams of potassium hydroxide in 240 ml. of distilled water was added thereto. The clear solution was heated at reflux temperature for a period of about 24 hours. At the end of that time, 2000 ml. of alcohol were distilled off and the residue was subsequently treated with about 2 kg. of ice. The resulting clear solution was adjusted to a pH of 5 to 6 with glacial acetic acid. The crude a-n-dodecyl-a-propyl-fi-aminopropionic acid was thus precipitated out of solution as a gum-like sinuous mass. This mass filtered with suction and washed well with water. The filtration residue was then dissolved in about 3000 ml. of isopropanol, following which the solution was filtered while hot. The hot filtrate was treated with about 750 ml. of distilled water and the resulting precipitate was dissolved by further heating. The solution was then allowed to stand at room temperature until the temperature thereof reached about 30 C. Thereafter, the solution was placed in a refrigerator and kept there overnight. The product which crystallized out, namely, a n dodecyl-u-propyl-/3-amino-propionic acid, was filtered off under suction, washed with cold isopropanol and pressed until as dry as possible. The product was placed in a vacuum oven at room temperature and retained therein until superficially dry, following which it was heated to a maximum temperature of 50 C. over phosphorous pentoxide and potassium hydroxide, to constant weight. Yield of theory.

The a-n-dodecyl-m-propyl-fl-amino-propionic acid which is thus obtained in a yield of about 90% theory in the form of a white to light yellow powder, melted at a temperature of about 239 C. with decomposition.

A thixotropic base material for lacquers and colors was obtained as follows: 10 grams of a-n-dodecyl-a-propylfi-amino-propionic acid, produced as described in the preceding paragraph, were heated in 1000 grams of petroleum ether. There was obtained a gelatinous viscous material into which a suitable lacquer material and colors were worked. These compositions do not discharge from containers, such as, for example, tubes. They adhere to the brush and can be readily spread.

The n-dodecyl-allyl-cyanoacetic acid ethyl ester which was used as the starting material in this example was obtained .as follows:

(c) 900 grams of cyanoacetic acid ethyl ester were added, at a temperature of 70 C. while stirring, to a solution of 92 grams of sodium in 1600 ml. of absolute ethyl alcohol. During the addition, or shortly thereafter, the sodium salt of the cyanoacetic ester precipitated out. Thereafter the mixture was heated to reflux temperature and, at an internal temperature of about 80 0, dropwise addition of 1000 grams of n-dodecy-l bromide was commenced while stirring. Subsequently, the reaction mixture was heated at reflux until a pH of 7 to 8 was reached. The alcohol was then distilled off under reduced pressure and the residue, after cooling to a temperature of about 30 C. (internal), was dissolved in 1000 ml. of ether, 500 ml. of water and about 500 grams of ice, stirred and separated. The aqueous phase was extracted an additional two times with 500 ml. of ether. The combined ether ex tracts were washed with water and saturated sodium chloride solution, dried and evaporated. A major portion of the excess cyanoacetic ester was then distilled off in a water-jet vacuum at a bath temperature of 160 C., allowed to cool to a temperature of about 50 C. (internal) and, subsequently, additional small amounts of cyanoaoetic ester and the other foreruns were distilled in high Vacuum. The n-dodecyl-cyanoacetic acid ethyl ester distilled over at a temperature of about 142 to 145 C./0.05-0. 1 mm. as a colorless liquid. The product was collected in a yield of 79% of theory.

The n-dodecyl-cyanoacetic acid ethyl ester, thus obtained, was added, while stirring at a temperature of about 60 to 70 C., to a solution of 72.8 grams of sodium in 1260 ml. of absolute ethyl alcohol. The sodium salt of the n-dodecyl-cyanoacetic acid ethyl ester precipitated out. Subsequently, while stirring, 458 grams of allyl bromide were added dropwise thereto so that the reaction mixture readily comes to boiling. After the addition, the reaction mixture was heated at reflux temperature (bath temperature 1'10" C.) until a pH of 7 to 8 was reached. The alcohol was then distilled off under reduced pressure and the residue worked up as described in the preceding paragraph. By subsequent distillation in high vacuum there was obtained the n-dodecyl-allyl-cyanoacetic acid ethyl ester (boiling range 135 to 140 C./0.03 mm.) as a colorless liquid in a yield of 93% of theory.

Example 2 By the hydrogenation of n-octyl-allyl-cyanoaeetic acid ethyl ester and the subsequent hydrolysis of the thus produced u-n-octyl-ot-propyl-p-amino-propionic acid ethyl ester, in the manner described in Example 1 hereof, there was obtained at-n-octyl-otpropyl- 8-amino-propionic acid, having a melting point of about 238 C. (with decomposition). The product was obtained in a yield of about 72% based on the n-octyl-allyl-cyanoacetic acid ester.

Example 3 By the hydrogenation of n-decyl-allyl-cyanoacetic acid ethyl ester and the subsequent hydrolysis of the thus produced a-n-decyl-ot-propyl-fi-amino-propionic acid ethyl ester, in the manner described in Example 1, there was obtained a-n-decyl-ix-propyl-fi-amino-propionic acid, melting point at about 238 C. (with decomposition) in a yield of about 70% to 75%, based on the n-decyl-allylcyanoacetic acid ester.

Example 4 By the hydrogenation of n-tetradecyl-allyl-cyanoacetic acid ethyl ester and the subsequent hydrolysis of the thus produced a-n-tetradecyl-ot-propyl-fi-amino-propionic acid ethyl ester, in the manner described in Example 1, there was obtained a-n-tetradecyl-a-propyl-,8-amino-propionic acid, melting point at about 240 C. (with decomposition) in a yield of 65% based on the n-tetradecyl-allyl-cyanoacetic acid ester.

Example 5 By the hydrogenation of n-tetradecyl-methallyl-cyanoacetic acid ethyl ester (boiling point at 154 C./'0.09 mm.) and the subsequent hydrolysis of the thus produced a-ntetradecyl-a-isobutyl-fi-amino-propionic acid ester (boiling point 163 C./0.04 mm.), in the manner described in Example 1, there was obtained ot-n-tetradecyl-a-isobutyl-B-amino-propionic acid, melting point at 217 C.- 221 C., with decomposition.

The product was found to be particularly Well suited for use as a thickening agent for non-polar organic solvents. The resulting solutions or gels are very homogenous with little colloid formation.

Example 7 By the hydrogenation of n-dodecyl-rnethallyl-cyanoacetic acid ethyl ester (boiling point 145 C./0.07 0.08 mm.) and the subsequent hydrolysis of thus obtained a-n-dodecyl-a-isobutyl-B-amino-propionic acid ethyl ester (boiling point at C./0.2 mm.) there was obtained a-n-dodecyl-ot-isobutyl-B-amino-propionic acid, melting point 234236 C. (with decomposition).

We claim:

1. An amino carboxylic acid having the general formula in which R is a saturated hydrocarbon residue selected from the group consisting of nonyl, decyl, undecyl, dodecyl, tetradecyl, hexadecyl, octadecyl, eicosyl and docosyl radicals; and in which R is a saturated hydrocarbon residue containing from 1 to 8 carbon atoms.

. ot-n-Decyl-a-propyl-B-amino-propionic acid.

. a-n-Dodecyl-ot-propyl-fl-amino-propionic acid.

. a-n-Tetradecyl-a-propyl-fi-amino-propionic acid.

. a-n-Tetradecyl-m-isobutyL/i-amino-propionic acid.

. a-n-Hexadecyl-ot-propyl-fi-amino-propionic acid.

. u-n-Dodecyl-a-isobutyl-fi-amino-propionic acid.

References Cited UNITED STATES PATENTS 3/1950 Lincoln 260-534 X FOREIGN PATENTS 3/ 1958 Great Britain.

OTHER REFERENCES Paul E. Gagnon et al.: Can. J. Chem, vol. 29, page 184 (1951).

NICHOLAS S. RIZZO, Primary Examiner.

F. A. MIKA, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No 3 ,328 ,436 June 27 1967 Gustav Erlemann et 211.

It is hereby certified that error appears in the above numbered pat ent requiring correction and that the said Letters Patent should read as corrected below.

Column 4, line 36, for "150" read 160 Signed and sealed this 15th day of April 1969.

(SEAL) Attest:

EDWARD J. BRENNER Edward M. Fletcher, Jr.

Commissioner of Patents Attesting Officer 

1. AN AMINO CARBOXYLIC ACID HAVING THE GENERAL FORMULA 